{62 -Ketoacyl derivatives of 6-aminopenicillanic acid and process thereof

ABSTRACT

Beta -Ketoacyl derivatives of 6-aminopenicillanic acid of the formula:   ARE DISCLOSED. In the above structure R1 is hydrogen, alkyl, halogen, alkoxy, cyano, trifluoromethyl and the like; Z is CHR2 or NR2; R2 is hydrogen, alkyl, aralkyl; M is an alkali or alkaline earth metal such as sodium, potassium, or calcium. These compounds are useful as anti-bacterials.

United States Patent Sircar et al.

[ Apr. 15, 1975 B-KETOACYL DERIVATIVES OF 6-AMINOPENICILLANIC ACID AND PROCESS THEREOF [75] Inventors: Jagadish C. Sircar, Dover; Harold Zinnes, Rockaway; John Shavel, Jr., Mendham, all of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plaines, NJ.

[22] Filed: Apr. 26, 1974 [21] Appl. No.: 464,707

[52] U.S. Cl 260/239.l; 260/243 R; 260/32682;

[51] Int. Cl C07d 99/14 [58] Field of Search 260/239.1

[56] References Cited UNITED STATES PATENTS 3,329,675 7/1967 Alburn et al l l 260/239.l 3,736,318 5/1973 McCaully et a1. 260/239.l

Primary ExaminerBernard Helfin Assistant Examiner-Gerald A. Schwartz Attorney, Agent, or FirmAlbert H. Graddis; Frank S. Chow; George M. Yahwak [57] ABSTRACT ,B-Ketoacyl derivatives of 6-aminopenici1lanic acid of the formula:

v N g L s CH3 1 Z 1'1 so? 0 cu COOM 2 Claims, N0 Drawings B-KETOACYL DERIVATIVES OF 6-AMINOPENICILLANIC ACID AND PROCESS THEREOF The present invention relates to semisynthetic peniinitially formed triethylammonium salt is converted to the dimetal salt by treatment with a metal salt of an organic acid such as Z-ethylhexanoic acid.

The starting compound II is commercially available.

cillins, and more particularly it relates to B-ketoacyl de- 5 The starting compounds lll are prepared by the followrivative of 6-amino-penicillanic acid of the formula:

III

. S Cll LNll 3 g l l N $01 0 ca,

CODi-l wherein R is hydrogen, alkyl, halogen, alkoxy, cyano. trifluoromethyl and the like; 2 is Cl-IR or NR R is hydrogen, alkyl, aralkyl; M is an alkali or alkaline earth metal such as sodium, potassium, or calcium.

"Alkyl and alkoxy as used in the specification and in the claims are meant to have l to 7 carbon. These include, for example, methyl, ethyl, propyl, isopropyl, butyl,' isobutyl and so on. Aralkyl encompasses alkyl as defined in which an aryl group of 6 to 10 carbon atoms is substituted for a hydrogen atom such as. for example, benzyl, phenethyl and the like.

The compounds I are useful as antibacterial agents. At concentrations of 31 to 500 m-cg/ml they inhibit S. aureus and at concentrations of 67-500 mcg/ml they inhibit N. gonorrlioeae.

These compounds are accordingly indicated in the treatment of infections caused by these susceptible organisms. Generally speaking the dose for treating such infections in an adult is about 500 mg to 1,000 mg orally or topically.

Compound I is formulated with dosage forms for oral or topical administration utilizing known pharmaceutical technology for preparing penicillin derivatives.

According to the process of this invention, 6-aminopenicillanic acid [I is reacted with an activated ester of structure lll, where R is hydrogen or N0 in the presence of a base such as triethylamine. The

H211 S H3 CO H OH l 00G R1 1. El: N III 5 C H I ing scheme:

An enamine of structure IV is reacted with phosgene to give the acid chloride V. This is not isolated as such but is reacted with a phenol of structure VI to form an enamine ester of structure Vll. Acid hydrolysis of Vll I gives the required activated ester Ill.

The preparation of the starting enamine IV is described by Zinnes, et al, J. Org. Chem. 31, 162 (1966) and in our patent application Serial Number 252, 163 (filed 5-5-72). The compound lll wherein R and R are hydrogen and Z is NC H is also described in the latter application.

In order to illustrate further the practice of this invention, the following examples are included. Temperature is given in degrees Centigrade.

EXAMPLE 1 KO i? cNH- $02 COOK Dipotassium 6-[ (4-Hydroxy-2-methyl-2H-l .2- benzothiazin-3-yl)formamido]penicillanate S,S- Dioxide. A solution of 3.2 g (0.015 mol) of 6- aminopenicillanic acid and 6.0 ml of triethylamine in 25 ml of dichloromethane was cooled to 0 and 5.6 g (0.0l5 mol) of p-nitrophenyl 4-hydroxy-2-methyl-2H- l,2-benzothiazine-3-carboxylate l,l-dioxide was added (as the solid powder) followed by 3.0 ml of additional triethylamine and 7.5 ml more dichloromethane. The reaction mixture was stirred at room temperature for hr after which time the infrared spectrum of a small sample indicated that there was no further decrease in the intensity of the ester carbonyl band at 1690 cm. Dilution of the reaction mixture with ml of ether resulted in separation of an oil. The solvent was removed by decantation, the oil was dissolved in 25 ml of dichloromethane, and reprecipitated by the addition of 100 ml of ether. This procedure was repeated twice more and the resulting oil was triturated with dry ether to give a brown solid (the triethylammonium salt) whose infrared spectrum showed bands at 1,760. 1,600, and l 172 cm, representing the B-lactam, amide and S0 groups, respectively. This crude salt was dissolved in 30 ml of methanol and 15 ml of a 2.4 molar was added. Dilution with 100 ml of ether resulted in EIOH 2 3 4 EXAMPLEZ p-Nitrophenyl 4-( l-pyrrolidinyl)-2H-lbenzothiopyran-3-carboxylate l,l-Dioxide. A solution of 6.0 g (0.06 mol) of phosgene in 55 ml of benzene was diluted with 30 ml of tetrahydrofuran and cooled to l. To this was added over a period of 30 min, a solution of 12.6 g (0.05 mol) of 4-(1- pyrrolidinyl)-2H-l-benzothiopyran 1,1-dioxide and ml of triethylamine in 400 ml of tetrahydrofuran and the reaction mixture was stirred at room temperature for 3 hr. lt was cooled to 40 and a solution of 7.7 g (0.055 mol) of p-nitrophenol and 12 ml of triethylamine in 50 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 16 hr, refluxed for 3 hr,'and most of the solvent was evaporated. It was treated with ice-water and extracted with dichloromethane. The dried dichloromethane phase was evaporated to an oily residue which became a gummy semisolid on trituration with several portions of ether. This gum was dissolved in dichloromethane. Slow distillation resulted in the crystallization of 13.0 g of'product, mp 17 ll 74 dec. Recrystallization from a mixture of 250 ml of tetrahydrofuran and 250 ml of isopropyl ether gave 10.7 g of material, mp l75-l78 dec.

Anal. Calcd for C H N O S: C, 57.96; H, 4.38; N,

6.76; S, 7.74. Found: C, 57.90; H, 4.64; N, 6.83; S, 7.98.

EXAMPLE 3 p-Nitrophenyl 4-Hydroxy-2H-l-benzothiopyran-3- carboxylate 1,1-Dioxide. A mixture of 7.0 g of pnitrophenyl 4-( l-pyrrolidinyl)-2H-l-benzothiopyran-3- carboxylate l,l-dioxide, 50 ml of glacial acetic acid, and 100 ml of 1N hydrochloric acid was heated on a steam bath for 20 min and diluted with ice-water. The resulting precipitate was collected and recrystallized from tetrahydrofuran-isopropyl ether to give 5.5 g of product, mp 206209. dec.

Anal. Calcd for C H NO S: C, 53.19; H, 3.07; N,

3.88; S, 8.87. Found: C, 53.19; H, 3.15; H, 3.64; S, 9.1 l.

COOK

Dipotassium 6[(4-Hydroxy-2H-l-benzothiopyran- 3yl)formamido]penicillinate S,S-Dioxide. A solution of 2.16 g (0.01 mol) of 6-amino penicillanic acid and 4 ml of triethylamine in 18 ml of dichloromethane was cooled to 0 and a solution of 3.8 g (0.0105 mol) of pnitrophenyl 4-hydroxy-2H-l-benzothiopyran-3- carboxylate l,l-dioxide and 2 ml of triethylamine in 10 ml of dichloromethane was added. The reaction mixture was stirred at 0 for one hour and then at room temperature for 20 hr after which time the infrared spectrum of a small sample indicated that the ester band at 1690 cm. had nearly disappeared. Dilution with ml of ether resulted in separation of an oil. The solvent was removed by decantation, the oil was dissolved in 20 ml of dichloromethane and reprecipitated by the addition of 50 ml of ether. This procedure was repeated twice more and the resulting oil was triturated with 50 ml of dry ether to give a yellow solid (the triethylammonium salt) whose infrared spectrum showed bands at 1760, 1605, and 1160 cm", representing the B-lactam, amide, and S0 groups, respectively. This crude salt was dissolved in 30 ml of methanol, 10 ml of a 2.4 molar solution of potassium Z-ethylhexanoate in n-butanol was added, and the solution was allowed to stand for 15 minutes. Dilution with ml of anhydrous ether resulted in precipitation of the desired potassium salt. This was redissolved in 20 ml of methanol and reprecipitated by the addition of 60 ml of ether. This dissolving and reprecipitation process was repeated, the crystalline precipitate was collected, triturated with ether, and dried in vacuo over phosphorous pentoxide at room temperature for 20 hr to give 3.0 g of product,

mp 235240dec.

v-" 3400, 1760, 1600, 1158 cm". A,,,,,,""" 236 (67,700), 338 (5,000) m;.:..

We claim:

1. A compound of the formula no if CNH s cu U N so; 0 ca 3 COOH 3-yl)formamido]penicillanate S,S,-dioxide. 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 which is dipotassium 6-((4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-yl)formamido) penicillanate S,S,-dioxide. 